Each of the billions of neurons in the human brain can have up to 10,000 synapses. By establishing a dynamic network of synaptic connections, the brain is able to attain the level of functional complexity that underlies human behavior. The efficiency of signal transmission at synapses is constantly being adapted in response to experience. This synaptic plasticity is critical for the fine-tuning of brain development as well a higher brain function such as learning and memory. The plasticity of synapses is modulated and maintained by processes that are sensitive to neuronal activity and astrocyte function. It is now clear that many neurological and psychiatric diseases result from defects in synaptic transmission and plasticity. Thus, understanding the mechanisms regulating synaptic transmission in the brain is critical for the development of therapeutic treatments for these diseases. The Conte Center will take several approaches to investigate the molecular and cellular mechanisms involved in the regulation of plasticity at the excitatory synapses. Richard Huganir will be examining the dynamics of receptor trafficking during synaptic plasticity in vivo i real time using two-photon microscopy. Sol Snyder will be analyzing how gaseous transmitters like NO and H2S modify AMPA receptor function and synaptic plasticity. David Ginty and Alex Kolodkin will be examining how the Sema3F-Npn-2/PlexinA3 signaling pathway regulates synaptic structure and function and AMPA receptor trafficking. Paul Worley will be analyzing how the Oral and STIM1 proteins control intracellular calcium stores and regulate synaptic plasticity in neurons and astrocytes. Dwight Bergles will be studying calcium signaling in astrocytes and how astrocytic signaling can regulate synaptic plasticity. David Linden will be examining the modulation of calcium transients in mossy fiber nerve terminals in the cerebellum and the effects of behavioral experience on presynaptic function using in vivo imaging techniques. All of these projects center on the synapse and address how presynaptic, postsynaptic and astrocytic mechanisms converge on the synapse to sculpt its morphology and function. Understanding these basic mechanisms of synaptic transmission and plasticity will provide insight into normal and abnormal brain function.